How blood flow is regulated, i.e., how perfusion is matched to tissue demands, is a central question in cardiovascular biology. The overall objective of the proposed studies is to develop quantitative theoretical models for oxygen transport and blood flow regulation in microvascular networks of skeletal muscle. The models will clarify the roles of mechanisms that coordinate changes in vascular resistance, will provide a rational structure for interpreting experimental data, and may suggest new therapeutic approaches for controlling tissue perfusion. The specific aims are:1. To develop theoretical models to predict distributions of vascular tone in microvascular networks of skeletal muscle. Equations will be developed to describe the dependence of vascular tone on metabolic factors, wall shear stress, pressure and conducted responses in vessel walls. These equations, combined with those of network hemodynamics, will be solved to predict tone and internal diameter of each segment.2. To combine theoretical models for oxygen transport with models for flow regulation, to describe how microvascular networks regulate flow in response to changes in oxygen demand. Theoretical simulations of oxygen transport in resting skeletal muscle will be developed based on observed network structures. Models for working muscle will be developed that take into account the organization of muscle fibers into motor units.3. To develop theoretical predictions of the relationship between whole-organ oxygen demand and perfusion in skeletal muscle, based on microvascular-level oxygen transport and flow regulation processes. Results obtained in aims 1 and 2 will be used to predict variation ofmacroscopic variables (flow, consumption, extraction, tissue oxygen level) with demand.In all these studies, particular emphasis will be placed on detailed comparisons of model predictions with experimental observations. This will be facilitated by the investigator's longstanding and close collaboration with experimental physiologists.